It is fast becoming clear that symptoms of psychiatric disorders, such as social avoidance, which are present in multiple conditions, may have singular neural dysfunctions underlying their presentation. Social abnormalities are present in autism, schizophrenia, depression and anxiety-related disorders, representing a significant portion of the population afflicted with mental disease. While many pharmacotherapies exist, the success rate of treating a majority of patients is surprisingly low. This highlights the urgency in studyin common symptoms across multiple models, while examining new brain circuits to parse out specific adaptations responsible for maladaptive behaviors. While the brain's dopamine system is clearly involved in psychiatric disorders, the brain's major neurotransmitter glutamate has also recently been implicated in underlying certain psychiatric symptoms, yet due to its ubiquity throughout the brain, its function has been difficult to determine. Many studies of the effects of stress on the brain have seen that it alters cell morphology and electrical properties, however many of these studies have occurred in discrete brain regions without knowledge of the input to the cell. With the advent of novel viral techniques and transgenic mouse lines it is now possible to isolate specific synapses, the point of communication between cells, to discover which glutamatergic pathways are involved in a specific behavior. In this proposal I will utilize two stress paradigms (a social and non-social) to isolate the effects of social stress on social reward processing. I will utilize manipulation of specific cells with light-activated ion channels and transgenic lines in combination with electrophysiology to study glutamatergic synapses of the thalamus impinging upon regions important in reward processing and social behavior, specifically the prefrontal cortex and nucleus accumbens. This proposal hypothesizes that social stress will have unique synaptic adaptations when compared to non-social stress and these adaptions are specifically involved in regulating social reward processing. Preliminary results demonstrate the involvement of thalamic cells synapsing on nucleus accumbens neurons in social interaction and the impaired acquisition of a social conditioned-place preference selectively by social stress. This study will seek to further understand how altering activity at these synapses can alleviate stress induced impairments in social behavior, as well as examining other thalamic based circuits that may regulate social behavior. The information gathered from these studies will provide novel starting points for developing unique therapies to alter circuit function and alleviate specific symptoms of psychiatric disorders.

Public Health Relevance

Alterations in social interactions is a hallmark characteristic of numerous psychiatric disorders, but the neurobiological adaptations responsible for this impairment are not well understood. My project seeks to understand how severe stress disrupts the processing of rewarding social interaction through the use of a social and non-social stress. By using these two distinct stressors, in conjunction with electrophysiology and expression of exogenous proteins to modulate cell activity, we will be able to dissect out which adaptions are specific to impaired social behavior as opposed to more general stress effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
3F32MH106206-02S1
Application #
9399000
Study Section
Program Officer
Desmond, Nancy L
Project Start
2016-12-01
Project End
2016-12-31
Budget Start
2016-12-01
Budget End
2016-12-31
Support Year
2
Fiscal Year
2017
Total Cost
$79
Indirect Cost
Name
Stanford University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Giardino, William J; Eban-Rothschild, Ada; Christoffel, Daniel J et al. (2018) Parallel circuits from the bed nuclei of stria terminalis to the lateral hypothalamus drive opposing emotional states. Nat Neurosci 21:1084-1095
Christoffel, Daniel J; Golden, Sam A; Walsh, Jessica J et al. (2015) Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nat Neurosci 18:962-4